Method and devices for transdermal delivery of lithium

ABSTRACT

A method and device for treating acute mania or bipolar disorder is disclosed, by transdermal delivery of Li +  at substantially constant rate through the skin via a dermal patch.

BACKGROUND OF THE INVENTION

[0001] As a mood stabilizing agent, lithium has a long history ofdocumented efficacy as well as risk associated with its use. Lithium hasthe narrowest gap between therapeutic and toxic concentrations of anydrug routinely prescribed in psychiatric medicine, and is poorlytolerated in one-third or more of treated patients. The incidence andseverity of toxicity associated with its use is related to the plasmaconcentration of Li⁺ and its rate of rise following conventional oralroutes of dosing. Lithium can be lethal in overdose and there is nospecific antidote for Li⁺ intoxication. The safety and tolerability ofLi⁺ could be dramatically improved by the use of a sustained, controlledLi⁺ delivery system.

[0002] Applicants have discovered a transdermal route of delivery as asuitable means of avoiding oral dosing “peaks” and symptomatic“troughs”, of minimizing the need for routine blood concentrationmonitoring, and of decreasing total daily doses, drug interactions, anddosing frequency. These advantages allow improved patient compliance andquality of life for patients treated with Li⁺. The well-recognizedmedical-legal liabilities associated with Li⁺ treatment aresubstantially changed, and allow an expanded use of Li⁺ as an effectivedrug in the treatment of disabling mood disorders and other psychiatricillnesses.

[0003] Lithium is a fixed monovalent cation and the lightest of thealkali metals (group 1a of the Periodic Table of the elements). Ofrelevance to the design of this device, Li⁺ has the highest energy ofhydration of the alkali metals and, as such, can substitute for Na⁺ (andto a lesser extent K⁺) for ion transport by biological systems. Lithiumis both electroactive and hydrophilic. Lithium is abundant in somealkali metal-spring waters and has numerous industrial applications.Trace amounts of Li⁺ are found in human tissues; typical human bloodplasma concentrations of Li⁺ are 17 μL.

[0004] Lithium has no known physiological effects in man. Unlike otherpsychotropic drugs, Li⁺ has no discernible psychotropic effects innormal man. The therapeutic efficacy of lithium in the treatment ofacute mania and the prophylactic management of bipolar(manic/depressive) disorder has been consistently demonstrated. Lithium,along with the recent addition of valproic acid (Depakote®, Trademark ofAbbot Laboratories, Inc.), are the only drugs currently approved by theUS Food and Drug Administration for the treatment of acute mania.Manic-depressive disorder (bipolar disorder) is a chronic, cyclingdisease that afflicts approximately 1-1.8% of the population. Manicsymptoms include hyperactivity, impaired judgment, insomnia, grandiosityand other delusions. Affected individuals exhibit severe functionalimpairments evidenced by alienation from family, friends, and coworkers;indebtedness; job loss; divorce; and other problems of living. Lithiumsalts were introduced into psychiatry in 1949 for the treatment of maniaand were accepted for this use in the United States in 1970. Evidencefor the efficacy of lithium salts in the treatment of mania and theprevention of recurrent symptoms of manic-depressive illness is nowhighly impressive. The additional use of lithium coadministration inaugmentation strategies has been used as a means of enhancing treatmentresponse to a wide range of psychiatric drugs. Both lithium carbonateand lithium citrate are currently in therapeutic use in the US.

[0005] In the nearly 50 years of accumulated clinical experience withLi⁺ no distinctly improved agent has emerged for the treatment of themorbidity and mortality of bipolar disorder. While it remains thefirst-line therapy for bipolar disorder, the oral administration of Li⁺is predictably associated with a large and diverse array of adverseeffects that impact negatively on patient compliance and safety. Theseevents are in turn well related to the pharmacokinetics of orallyadministered formulations. Symptomatic states related to interdoseconcentration “troughs” or inadvertent noncompliance further exacerbatesnoncompliance. Only one-third of patients in a recent community samplewere estimated to be compliant. The development of sustained or slowrelease Li⁺ preparations represents a direct response to the limitationsof oral routes of lithium salt administration. However, the performanceof these preparations vary between manufacturers and between batches andthey are often used in divided daily dosing strategies similar tononsustained release preparations. Extremely slow release preparationsare furthermore associated with pronounced GI irritation. Availablesustained release formulations represent an imperfect solution to thelimitations of oral lithium dosing. There is thus a clinical need for analternative dosing strategy for Li⁺ that is not met by currentlyavailable preparations. The device and methods of the present inventionoffer a novel strategy of transdermal Li⁺ delivery to enhance the safetyand efficacy of a drug of documented effectiveness and value inpsychiatric practice.

[0006] The device of the present invention was developed to meetpharmacoldnetic inadequacies of the use of conventional oral dosingstrategies that limit therapeutic applications of lithium in clinicalmedicine. Such limitations include acute and long term toxic reactions,the emergence of breakthrough symptoms, poor patient compliance, thenecessity of therapeutic drug monitoring and a lack of safety inoverdose situations. A transdermal delivery system for lithium accordingto the present invention is suitable for these purposes.

BRIEF DESCRIPTION OF THE INVENTION

[0007] A method of administering Li⁺ to a patient at substantiallyconstant rate without causing significant pain or tissue damage isdisclosed. The method involves the attachment of a dermal patch to thepatient, wherein the patch delivers Li⁺ in response to a current,desirably a direct current, even more desirably a pulsed direct current,presumably by iontophoresis. Also disclosed is a dermal patch for use inthe method of the present invention. The method and the patch aresuitable for the treatment of acute mania, bipolar (manic/depressive)disorder, and other psychiatric illnesses susceptible to treatment withlithium, and is particularly adaptable to long-term administration andtreatment.

[0008] The transdermal delivery of lithium to the systemic circulationis based on the application of patch technology incorporating aniontophoretic form of electrically assisted drug delivery. In aparticular embodiment of the invention, the device uses direct current(dc), desirably pulsed, anodal iontophoretic lithium delivery, withpatch placement typically at a site rich in sweat glands, such as at anaxillary site. Controlled lithium delivery is dose adjustable andprogrammable as a function of the applied current density.

[0009] The device and method of the present invention allow theadministration of lithium ion to the bloodstream within the therapeuticwindow without peaks (creating damage of toxicity) and troughs (creatingthe danger of breakthrough symptoms and decreased patient compliance)experienced with conventional methods of lithium administration. Lithiumis controllably delivered across at least the stratum corneum, andpossibly other layers of the epidermis, using an unobtrusive device thatrequires minimal compliance activity on the part of the patient.

BRIEF DESCRIPTION OF THE FIGURES

[0010]FIG. 1 is a graph setting forth a typical profile of blood Li⁺concentration in patients using conventional oral dosing, andillustrates the highly variable concentration that is the source of muchof the known toxicity in patients.

[0011]FIG. 2 schematically illustrates one embodiment of the dermalpatch of the present invention, in cross section.

[0012]FIG. 3 is a plan view of one embodiment of the present inventionshowing the arrangement of the current distribution member.

DETAILED DESCRIPTION OF THE INVENTION

[0013] The present invention relates to a dermal patch for administeringlithium to a human patient at substantially constant rate withoutcausing significant pain or tissue damage, which patch comprises:

[0014] a source of lithium for iontophoretic delivery;

[0015] a support for said lithium source;

[0016] a current distribution member for delivering a pulsed directcurrent sufficient to iontophoretically deliver lithium across a stratumcorneum layer of the epidermis of said human, said current distributionmember comprising an electrochemically active component in electricalconnection with a battery, a voltage pulse generator and a precisionresistor.

[0017] In one embodiment of the present invention, the electrochemicallyactive component of the dermal patch comprises an Ag/AgCl mesh. Thisalso helps to minimize skin irritation and/or discoloration.

[0018] In another embodiment of the dermal patch of the presentinvention, the source of lithium is LiCl, lithium carbonate, or lithiumnitrate, or combination thereof.

[0019] In another embodiment of the dermal patch of the presentinvention, the support for the lithium source comprises a drugreservoir, a tamper-proof occlusive backing, a conductive gel, and amembrane permeable to Li⁺ suitable for contact with the skin, andoptionally an adhesive. The adhesive is suitable for reversiblyattaching said patch to the epidermal layer of the skin of the patient.

[0020] In another embodiment of the dermal patch of the presentinvention, Li⁺ source is not buffered. This helps to avoid or reducedecreases in transdermal iontophoretic drug flux due to competing ions.

[0021] In another embodiment of the dermal patch of the presentinvention, a detoxification or neutralization effective amount of acompleting agent selected from the group consisting of EDTA, EGTA, andpharmaceutically acceptable salts thereof is included in the patch. Thiscomplexing agent is typically included in the occlusive backing, so thatit detoxifies or neutralizes the lithium in the event that the backingis damaged or ruptured.

[0022] In another embodiment of the dermal patch of the presentinvention, the patch is substantially free of skin permeabilityenhancers, including organic solvents, such as ethylene glycol. However,while not necessary, skin permeability enhancers may be used if desired.

[0023] Another embodiment of the present invention is dermal patch foradministering lithium to a human patient at substantially constant ratewithout causing significant pain or tissue damage, which patchcomprises:

[0024] a source of lithium for iontophoretic delivery;

[0025] a support for said lithium source;

[0026] a current distribution member for delivering a pulsed directcurrent sufficient to iontophoretically deliver lithium across a stratumcorneum layer of the epidermis of said human, said current distributionmember comprising an electrochemically active component in electricalconnection with a battery, a voltage pulse generator and a precisionresistor; and

[0027] a detoxification or neutralization effective amount of acomplexing agent selected from EDTA or EGTA or pharmaceuticallyacceptable salts thereof, wherein the lithium source is unbuffered; and

[0028] wherein the patch is substantially free of any skin permeabilityenhancers.

[0029] Another embodiment of the present invention is a method oftreating acute mania or bipolar (manic/depressive) disorder withlithium, by providing and maintaining blood Li⁺ concentrations ofbetween about 0.6 and about 1.4 mEq/L in humans in need thereof, whichmethod comprises the steps of

[0030] (a) providing a dermal patch for administering lithium to apatient at substantially constant rate;

[0031] (b) attaching the patch to the patient's skin;

[0032] (c) iontophoretically delivering Li⁺ from said patch to thepatient. This embodiment of the invention can further comprisemonitoring the blood Li⁺ concentrations and adjusting the dose rate ifnecessary to provide and maintain blood Li⁺ concentrations of betweenabout 0.6 and about 1.4 mEq/L.

[0033] This method can use the dermal patch described above foradministering lithium to a patient at substantially constant ratewithout causing significant pain or tissue damage.

[0034] More particularly, the method of this embodiment of the presentinvention comprises providing and attaching a patch that comprises:

[0035] a source of lithium for iontophoretic delivery;

[0036] a support for said lithium source;

[0037] a current distribution member for delivering a pulsed directcurrent sufficient to iontophoretically deliver lithium across a stratumcorneum layer of the epidermis of said human, said current distributionmember comprising an electrochemically active component in electricalconnection with a battery, a voltage pulse generator and a precisionresistor.

[0038] In these embodiments of the method of the present invention:

[0039] the electrochemically active component of the patch can comprisean Ag/AgCl mesh, in order to minimize skin irritation and discoloration;

[0040] the source of lithium may be LiCi, lithium carbonate, or lithiumnitrate, or a combination thereof;

[0041] the support for lithium in the patch may comprise a drugreservoir, a tamperproof occlusive backing, a conductive gel, and amembrane permeable to Li⁺ suitable for contact with epidermal layer ofthe skin, and optionally an adhesive to reversibly attach said patch tothe epidermal layer of the skin of the patient;

[0042] the lithium source may be unbuffered, in order to avoid or reducedecreases in transdermal iontophoretic drug flux resulting fromcompeting ions;

[0043] a detoxification or neutralization effective amount of acomplexing agent selected from the group consisting of EDTA, EGTA, andpharmaceutically acceptable salts thereof can be added, desirably to theocclusive backing; and

[0044] the Li⁺ composition may be substantially free of skinpermeability enhancers, such as ethylene glycol.

[0045] Another embodiment of the present invention relates to a methodof treating acute mania or bipolar (manic/depressive) disorder withlithium, by providing and maintaining blood Li⁺ concentrations ofbetween about 0.6 and about 1.4 mEq/L in humans in need thereof, whichmethod comprises the steps of:

[0046] (a) providing a dermal patch for administering lithium to apatient at substantially constant rate without causing significant painor tissue damage;

[0047] (b) attaching the patch to the patient's skin;

[0048] (c) iontophoretically delivering Li⁺ from said patch to thepatient;

[0049] wherein the dermal patch for administering lithium to a patientat substantially constant rate comprises:

[0050] a source of lithium for iontophoretic delivery;

[0051] a support for said lithium source;

[0052] a current distribution member for delivering a pulsed directcurrent sufficient to iontophoretically deliver lithium across a stratumcorneum layer of the epidermis of said human, said current distributionmember comprising an electrochemically active component in electricalconnection with a battery, a voltage pulse generator and a precisionresistor; and

[0053] a detoxification or neutralization effective amount of acomplexing agent selected from the group consisting of EDTA, EGTA, andpharmaceutically acceptable salts thereof;

[0054] wherein the patch lithium source is unbuffered, and

[0055] wherein the patch is substantially free of skin permeabilityenhancers.

[0056] Another embodiment of the present invention relates to method oftreating in humans acute mania or bipolar (manic/depressive) disordercomprising the steps of

[0057] (a) topically applying to the skin of a patient in need of suchtreatment a transdermal delivery system comprising a source of lithium,and

[0058] (b) delivering an effective amount of lithium ion to thepatient's bloodstream.

[0059] Another embodiment of the present invention relates to a methodfor administering lithium at a substantially constant rate withoutcausing significant pain or tissue damage to a human patient in needthereof, which method comprises:

[0060] (a) providing a source of iontophoretically deliverable lithium;and

[0061] (b) iontophoretically delivering Li⁺ to said patient.

[0062] This method may further comprise monitoring the blood Li⁺concentrations and adjusting the dose rate if necessary to provide andmaintain blood Li⁺ concentrations of between about 0.6 and about 1.4mEq/L. The source of iontophoretically deliverable lithium used in thismethod may be a dermal patch. In particular, the dermal patch maycomprise a current distribution member capable of delivering currentsufficient to iontophoretically deliver Li⁺ across at least the stratumcorneum layer of the human epidermis. This current may be directcurrent, and more particularly may be pulsed direct current. The currentmay have a density in the range of from about 50 to about 350 μA/cm²,desirably between about 50 and about 200 pA/cm², and when pulsed mayhave a pulse frequency between about 1 and about 10 kHz, moreparticularly about 4 kHz. The dermal patch used in this embodiment ofthe present invention may have an on:off ratio duty cycle between about1 and about 99%, more particularly about 75%.

[0063] Desirably, the method of this embodiment of the invention uses apatch wherein the current distribution member does not cause or reducesskin irritation or discoloration or both. This can be achieved using anAg/AgCl mesh as the current distribution member.

[0064] 1. Clinical Parameters of Lithium Therapy in the Treatment ofManic Depression and Related Disorders

[0065] The probability of attaining a therapeutic response to Li⁺ isrelated to the obtainment of blood Li⁺ concentrations within a“therapeutic window” of 0.6-1.4 mEq/L (determined at steady-state 9-12hours following the previous nighttime dose). Blood serum concentrationsof Li⁺ less than 0.6 mEq/L are associated with a significantly higherrate of relapse of symptoms of bipolar illness and poorer psychosocialfunctioning, while concentrations higher than 1.4-1.5 mEq/L areassociated with a higher incidence of adverse events. Lithiumprophylaxis for the treatment of bipolar disorder is typically initiatedwith the assumption that treatment will be life-long. Thediscontinuation of lithium prophylaxis is not only associated withvirtual certainty of relapse, but may be associated with subsequentrefractoriness of symptoms to Li⁺. Typical therapeutic doses of lithiumsalts range from about 300 to about 2,400 mg/day (about 55-440 mg Li⁺ ),preferably about 300 to about 1,800 mg/day, and are often administeredin two or three divided daily doses. Higher doses are used in themanagement of acute manic symptoms. Daily doses lower than those used inthe treatment of acute mania are often used in prophylactic symptommanagement and in augmentation strategies. Available oral formulationsof lithium salts include syrup and both immediate and slow-release pillforms.

[0066] 2. Toxicology

[0067] The clinical use of Li⁺ is associated with a very narrow marginof safety. The ratio (therapeutic index) between Li⁺ concentrationsassociated with toxic and therapeutic effects only differs by a factorof 2 or 3. Lithium has multiple organ effects including actions on thefunction of the brain, thyroid, kidney, and heart. Lithium toxicity isrelated to the maximal plasma concentration (C_(max)) and its rate ofrise following oral administration. Acute intoxication is characterizedby vomiting, profuse diarrhea, coarse tremor, ataxia, coma, andconvulsions. Symptoms of milder toxicity that are associated with theabsorptive peak of Li⁺ include nausea, diarrhea, abdominal pain,sedation and fine tremor. Lithium-induced polydipsia and polyuria arecommon. Serious adverse effects related to Li⁺ actions on the nervoussystem include confusion, hyperreflexia, gross tremor, dysarthria,seizures, coma and death. These effects warrant the cautious use of Li⁺in the medically ill. Adverse effects of Li⁺ increase greatly when serumconcentrations exceed 1.5 mEq/L. Plasma Li^(+c) concentrations exceeding3.5 mEq/L are associated with life-threatening intoxication. The lowtherapeutic index for Li⁺ and the known relationship between circulatingLi⁺ concentrations and therapeutic and toxic effects necessitates thefrequent monitoring of serum or plasma Li⁺ concentrations. An additionallimitation to the use of oral lithium administration is the emergence of“breakthrough” manic symptoms associated with “trough” Li⁺concentrations in the later stages of drug elimination.

[0068] Drug interactions associated with the concomitant administrationof other drugs with Li⁺ relate largely to alterations in sodium balance.

[0069] 3. Pharmacokinetics

[0070] The pharmacokinetics of lithium salts following their oraladministration as their solid or liquid dosage forms is wellcharacterized.

[0071] As for the absorption properties of lithium salts, a completedissociation of the lithium salts into their ions occurs after oraladministration. Li⁺ is readily and nearly completely absorbed from thegastrointestinal tract. For immediate release formulations, the time tomaximal plasma Li⁺ concentration (T_(max)) occurs 1-4 hours following anoral dose and attain C_(max) values of about 3-20 mEq/L.

[0072] In the distribution of lithium salts, Li⁺ does not bind to bloodproteins. The final volume of distribution (V_(d)) is 0.7-0.9 L/kg andapproximates that of total body water.

[0073] In the elimination of lithium salts, Li⁺ is excreted primarily(>90%) through the kidneys and Li⁺ clearance correlates with renalfunction. Elimination of Li⁺ through sweat, saliva, and feces accountsfor less than 5% of an oral dose. The half-life of Li⁺ ranges from 18 to36 hours. Eighty percent of the filtered load of Li⁺ is reabsorbed inthe renal proximal tubules in tandem with Na⁺.

[0074] Li⁺ is not biotransformed, and is not subject to metabolicconversion.

[0075] 4. Advantages of Transdermal Lithium Delivery to the SystemicCirculation

[0076] The general advantages of transdermal drug delivery relative tooral dosing include controlled drug concentrations in the bloodstream,the avoidance of the gastrointestinal tract and hepatic first-passmetabolism, control of absorption, availability of multiple skin sitesto avoid local irritation and toxicity, and improved patient compliancedue to simpler dosing regimens. Multiple possible routes of transdermaldelivery are also available depending on the size, charge, polarity, andpotency of the drug to be delivered. The clinical use of lithium willclearly benefit from controlling Li⁺ concentrations in the bloodstream,to avoid oral dosing “peaks” and decrease systemic toxicity, GI relatedside effects, and improve patient compliance. Specific properties of Li⁺and of human skin are suitable for an effective mechanism of transdermaldelivery of Li⁺ to the systemic circulation.

[0077] 5. The Skin as a Barrier to Transdermal Drug Delivery

[0078] The human skin is the largest organ of the human body, coveringan area of about 2 m² and composing one-sixth of the total body weight.The skin represents the primary defense against invading microorganisms,chemical and mechanical trauma, and UV irradiation. Skin is alsoessential for the protection of the internal fluid and electrolyteenvironment of the body. The skin is also a formidable barrier to thetranscutaneous delivery of drugs. Human skin varies in thickness from0.5 to 6 mm depending on the part of the body that it covers. A densevascular supply to the skin exists about 0.2 mm below its surface and isinvolved in essential homeostatic functions such as thermoregulation.Human skin has a pH of 3-4 and thus possesses a net negative charge atphysiological pH. The relevant result of this net negative charge isthat the skin is permselective, i.e., it allows the transport ofpositively charged species such as Li⁺ to proceed with less resistancethan that of a negatively charged molecule, due to the Donnan exclusionof co-ions.

[0079] The use of human skin as a large permselective surface area inclose proximity to the systemic circulation for transdermal Li⁺ deliveryis opposed by the outer layer or epidermis of the skin. The epidermis isan avascular stratified cell layer averaging about 0.1-0.2 mm inthickness. The innermost layer of the skin, the dermis, is vascularizedwith a high density of capillary loops immediately below thedermalepidermal junction in the papillary layer. Piercing the roughlyparallel dermis and epidermis are appendages such as hair follicles andsweat glands, the density of which varies over the surface of the body.

[0080] The actual barrier to the transdermal transport of Li⁺ (and otherdrugs) is the stratum corneum, the external layer of the epidermis.Relative to the stratum corneum, the transport of ions in the underlyingepidermis and dermis approximate freely diffusable conditions. Thestratum corneum has a thickness of only about 10-20 μm and consists of15 to 20 layers of densely packed hexagonal, disclike cells (about 1 by30 μm, also known as corneocytes) separated by thin multilamellar lipidbilayers that contain cholesterol free fatty acids, and ceramides.Corneocytes are composed of insoluble alpha-keratin filaments and are50% water-filled under hydrated circumstances. The lamellar bilayerzones separating the corneocytes are about 50 nm in thickness andpossess a small amount of bound water. In combination, the denselypacked hexagonal, disclike cells (or corneocytes) “bricks” and bilayerlipid region “mortar” function to hinder the transdermal transport ofboth lipophilic and hydrophilic substances.

[0081] In addition to these structural features, the stratum corneum ofthe human skin exhibits relevant electrical properties of resistance(10⁴-10⁶ ohm cm²) and capacitance (1-50 nF/cm²) that influence skinpermeability.

[0082] Molecular size of a drug is a major determinant of iontophoreticflux. The charge and molecular size of Li⁺ and the electrical propertiesof the stratum corneum facilitate the transdermal iontophoretic flux ofLi⁺ down electric and concentration gradient fields, also aided byelectroosmotic flow. Different drugs and distinct forms of transdermaltransport utilize one or at best several of the available routes totransdermal delivery. As a drug for transdermal delivery, Li⁺ is perhapsunique in that it represents a substrate for virtually every availablepathway of the intercellular/shunt and transcorneocyte routes ofdelivery through the epidermis. These properties of Li⁺ make it suitablefor attaining the large iontophoretic flux necessary for therapeuticdosing using the transdermal device.

[0083] 6. Characteristics of a Transdermal Lithium Delivery Device (theLithium Patch)

[0084] The long history of clinical experience with the oral dosing oflithium salts provides clear guidelines for the desired performance of atransdermal Li⁺ delivery device. Ineffective, therapeutic and toxiccirculating Li⁺ concentrations have been identified and define thewindow of desired Li⁺ delivery. Separate dosing requirements of the useof Li⁺ in the treatment of acute manic symptoms and the long-termmanagement of bipolar disorder have been defined. Patch-type transdermaldrug delivery devices of the present invention incorporate into theirdesign the desired performance features of an iontophoretically-assistedtransdermal Li⁺ patch.

[0085] A. Performance

[0086] Oral dosing with lithium salts results in the well-recognized“saw-tooth” patterns of blood Li⁺ concentration-time functions. (SeeFIG. 1.) Such patterns are characterized by marked inter- andintra-individual variability in T_(max) and C_(max), which arepharmacokinetic parameters related to the incidence and magnitude ofadverse drug effects. The transdermal iontophoresis of Li⁺ allows thecontrolled delivery of a sustained Li⁺ concentration in the systemiccirculation. The resulting decrease in intra- and inter-subjectvariability of Li⁺ pharmacokinetics decreases systemic toxicity, andminimizes the need for therapeutic drug monitoring with associatedvenipuncture. The pharmacodynamic outcome of the clinical use of thetransdermal Li⁺ patch is significantly smaller daily doses compared tooral dosing of Li⁺.

[0087] The transdermal Li⁺ patch allows a controlled delivery of 40 to240 mg Li⁺ /day to the systemic circulation. Dosage is selectable inapproximately 20 mg increments based on the applied current. A range ofapplied current densities of about 50 to about 350 μA/cm² provides theiontophoretic driving force. Each patch would have a performancelifetime of 33 to 200 hours, depending on the desired delivery rate.

[0088] It is preferable to have a battery source with a lifetimeslightly longer than the performance lifetime, to minimize any confusionover the suitability and the feasibility reapplying the patch to thepatient.

[0089] B. Patch Components and Their Schematic Organization

[0090] The components of one embodiment of the transdermal Li⁺ patch ofthe invention include the electrode, battery (constant voltage supply),drug reservoir, adhesive, Li⁺ permeable membrane, conductive gel, andtamper-proof occlusive backing containing a Li⁺ complexing agent. Theprecise nature of adhesive, conductive gel, and occlusive backing arenot critical to the present invention, provided that they are suitablematerials known in the art for transdermal patches and for iontophoreticdelivery systems. For example, the adhesive may be anypressure-sensitive, biomedical adhesive suitable for adhering to skin.The occlusive backing may be any suitable material for continuing alithium salt solution in a “tamper-proof” manner, and may be, e.g., aplastic material. The conductive gel and porous membrane may be anysuitable gel or membrane for use in iontophoresis.

[0091] In one embodiment of the patch of the present invention, there isa source of lithium to be iontophoretically delivered, comprising LiCi,lithium carbonate, or lithium nitrate, or combination thereof A support1 according to FIG. 2 comprises a drug reservoir 2, an occlusive backing3, preferably a tamper-proof occlusive backing, a conductive gel 4, amembrane 5 permeable to Li⁺ to contact the skin, and, optionally,adhesive 6 to attach the patch to the skin of the patient. FIG. 1 showsthe drug reservoir situated opposite the electrochemically activecomponent from the skin, however it will be recognized that thereservoir may be on the “skin side” of the electrochemically activecomponent, e.g. between the electrochemically active component and theconductive gel or permeable membrane.

[0092] A current distribution member in the patch comprises anelectrochemically active component 7, and a battery 8. Theelectrochemically active component 7 comprises silver or platinum in avariety of configurations, but in one embodiment is preferably a Ag/AgClmesh. The battery 8 is connected to the electrochemically activecomponent typically by a voltage pulse generator and a resistor (notshown).

[0093] The drug reservoir has a total volume of between about 5 ml andabout 30 ml, preferably about 10 ml. The reservoir contains anunbuffered electroneutral aqueous solution of LiCl, lithium carbonate,or lithium nitrate, preferably LiCl. An initial reservoir concentrationof 5 M LiCl is well within the solubility limits (i.e., 595 mg/ml) ofLiCl, provides a concentration gradient field, and permits a multidaylifetime for a patch. As a fixed cation, the oxidation state (i.e., +1)of Li⁺ is independent of solution pH. Therefore, the addition ofbuffering agents to maximize drug charge state by controlling solutionpH is not necessary, thus avoiding the decrease in transdermaliontophoretic drug flux by competing ions contributed by the bufferingagent and maximizing the transport number for Li⁺.

[0094] The electrode to be used for anodal iontophoresis comprisessilver or platinum, preferably as Ag/AgCl electrode mesh. The selectionof this anode material is based on the lack of pH change of the contentsof the drug reservoir by electrolysis during iontophoresis. Localizedskin irritation and discoloration are minimized and Li⁺ delivery isoptimized due to the lack of formation of more iontophoretically mobilebydronium ions.

[0095] The pulsed dc electrical field representing the iontophoreticdriving force for Li⁺ delivery is generated by a battery, voltage pulsegenerator and precision resistor. The battery represents typically aconstant source of between about 0.25 V and about 10.0 V, preferablybetween about 0.5 V and about 2.5 V, most preferably about 1 V. Aconstant voltage permits variation in the applied current with thechanging resistance of the skin. The selection of pulsed rather thancontinuous dc minimizes skin irritation, and maximizes iontophoreticflux during lengthy current application. The disadvantage of continuousdc for transdermal drug iontophoresis is skin polarization and relatedskin irritation and reduced drug flux with long durations of currentapplication. Buildup of this polarizable current can be reduced by theuse of pulsed dc. To minimize the pulse current density in obtaining thedesired time-average applied currents while allowing skin depolarizationbetween pulses, the typical parameters needed are a pulse frequency ofbetween about 1 and about 10 kHz, preferably about 4 kHz, and an on:offratio duty cycle of between about 1 to about 99%, preferably about 75%.

[0096] The transdermal Li⁺ patch has a surface area of between about 15cm² and about 40 cm², preferably about 25 cm², with a thickness ofbetween about 15 mm and about 18 mm. The proposed configuration of patchcomponents is viewed in cross section in FIG. 2.

[0097] The elements described above can be used in connection with acathode electrically connected to the current source via a circuit. Forexample, a separate cathode patch can be applied to the skin and itselectrode connected to the current source via an electrically conductivewire or lead through the occlusive backing.

[0098] Alternatively, the cathode may form an integral part of thedermal patch, e.g. as an annular ring of Ag/AgCl separated from andsurrounding the anode, and connected to the current source viaconductive wire disposed in the occlusive backing. Such an arrangementis shown by FIG. 3, which shows electrochemically active component 7 tocomprise an anode 8 as the inner portion, a cathode 9 as the outerportion, and optionally an insulating material 10, disposed between theanode and the cathode. The cathode material may be any material suitablefor an iontophoretic cathode, but is desirably Ag/AgCl. Any suitableinsulating material may be used as insulating material 10. It will beunderstood that the electrochemically active component 7 may also bearranged with the cathode in the center and the anode surrounding it, sothat in FIG. 3, the cathode would be represented by numeral 8 and theanode by numeral 9. It will also be understood that other shapes thanrectangular may be used for the anode and cathode, including, forexample, circular or ellipsoid shapes. It will also be understood thatthe various electrodes may be located in different layers of the dermalpatch. For example, the cathode may be located in a layer closer to theskin than is the anode, e.g., on the skin side of the conductive gel orof the porous membrane. In such an arrangement, an insulating material10 may be largely unnecessary.

[0099] While not wishing to be bound by any theory, it is believed thatthe Ag/AgCl anode is sacrificial, i.e. at least the metallic silvercomponents dissolve into the reservoir as silver ion. This silver ionreacts with the anionic counterion of the lithium salt in the reservoir,typically chloride ion, to form insoluble silver chloride. The decreasein chloride ions promotes diffusion of the Li⁺ cations through theopenings in the anode mesh and into the conductive gel, where theelectric field imposed by the anode provides the driving force formoving these cations across the stratum corneum and, desirably, into thesweat glands. The constant migration of lithium cations out of theconductive gel, through the porous membrane, and into the skin creates aconcentration gradient across the anode sufficient to overcome anyelectrostatic force exerted on the lithium cations by any portions ofthe electrostatic field that might tend to force them back into thereservoir and away from the anode. The result is that the lithiumcations move out of the reservoir and across the anode by diffusionresulting from the concentration gradient across the anode, and are thenpropelled away from the anode and through the conductive gel, porousmembrane, and epidermis by the electrostatic force exerted by theelectric field in the vicinity of the anode.

[0100] C. Dosing Features

[0101] The steady state iontophoretic flux of Li⁺ (J_(Li)) isproportional to the applied current density, I_(T):

J _(Li) =I _(T) t _(Li) /Z _(Li) F

[0102] where t_(Li) refers to the transport number for Li⁺, Z_(Li) thecharge (+1) of the lithium ion, and F the Faraday constant.

[0103] A linear increase in the iontophoretic delivery rate of Li⁺, andof numerous other inorganic and organic compounds, with increases in theapplied current density has been demonstrated. This linear relationshipallows a precise control of transdermal iontophoretic Li⁺ flux andpermits the preprogrammed delivery of Li⁺ from a skin patch.

[0104] D. Recommended Use

[0105] One preferred transdermal Li⁺ patch is intended for replacementon a daily basis. This recommended schedule of daily replacement isintended to facilitate a routine and more reliable patient use, and tominimize local skin reactions. A much longer functional life of thepatch increases the likelihood of inconsistent patch replacement, aresult that should be avoided in the symptom management of the patientswith the device.

[0106] A major route of transdermal Li⁺ flux occurs via an appendagealpathway consisting of iontophoretic delivery through the sweat glandduct and subsequent intradermal transport by substitution for sodiumtransport in the duct. Therefore, the sweat gland-rich axillary region(i.e., >200/cm²) represents a recommended site of patch placement. Useof this inconspicuous underarm site should also promote patch use.

[0107] For monitoring of Li⁺ concentration, initial patch application isfollowed within about 48 to about 72 hours by the collection of a venousblood sample to determine the blood Li⁺ concentration associated withthe initial applied current, and to adjust the current density ifnecessary. A second blood Li⁺ concentration determination is performedabout at least 2 weeks later to assure reliable patch performance andpatient compliance, and thereafter repeated as desired. The transdermalLi⁺ patch is not intended to substitute for the clinical monitoring ofsymptoms and drug side effects.

[0108] E. Safety and Tolerability

[0109] Lithium can be lethal in overdose and lithium has a long historyof involvement in suicide. The patch improves greatly the risksassociated with intentional or inadvertent Li⁺ overdose by decreasingthe accessibility of Li⁺. A durable occlusive backing hinders access tothe drug reservoir. Further, it is preferred to include a Li⁺ complexingagent sandwiched between the backing and drug reservoir, so that theagent is released into the reservoir if the patch is damaged.

[0110] The patch is suitable for daily long term use in the managementof acute mania and prophylaxis of bipolar disorder. It is also suitablefor augmenting the effects of other psychiatric drugs. Patchtolerability in long term use is addressed by the use of biocompatiblecomponents for the electrode, conductive gel and adhesive. The use of aconductive gel prevents skin “breakdown” due to direct electrode contactwith the skin. Skin irritation or damage is also minimized by the dailyrotation of patch placement to the other and opposite axillary site.Unlike many other available transdermal drug delivery devices, the patchdoes not use, and is substantially free of, skin irritating organicsolvents as permeability enhancers including, e.g., ethylene glycol.

[0111] An important limitation to long term tolerability of the patch islocalized sensation, pain or muscle stimulation due to the skinapplication of an electrical field. The applied current density andfrequency to be used as the iontophoretic driving force for transdermalLi⁺ delivery are selected to remain below accepted threshold values formuscle stimulation, sensation or pain. The stimulation of nerves byelectric fields that exceed a perception threshold can result inpainless sensations described most often as tingling or itching; painthresholds are generally 3-215 times greater than perception thresholds.A current density of about 500 μA/cm² is the approximate limit fortolerated sensation. See, e.g. Prausnitz, M. R., Advance Drug DeliveryReviews 18, 395 (1996). The largest time-average current densityproposed for the management of acute mania by transdermal Li⁺ deliveryrepresents a density that is 70% of this limit. Furthermore, the impactof localized sensations related to drug iontophoresis on thetolerability of the patch should be lessened by an increase inperception thresholds with time, and the use of pulsed dc iontophoresis.The lower current densities (<200 μA/cm²) are suitable for the long termprophylaxis and lithium augmentation strategies of the presentinvention.

[0112] F. Particular Embodiments Relating to Safety and Tolerability.

[0113] In typical embodiments of the patch technology of the presentinvention, no buffering agents for Li⁺ are needed, since it is notnecessary to avoid decreases in transdermal iontophoretic drug flux bycompeting ions. Another alternative feature of the present invention isthe incorporation of complexing agents, such as EDTA or EGTA, fordetoxification or neutralization. Still another embodiment is a patchwithout skin permeability enhancers. The choice of the appropriateorganic solvent for such a patch without skin permeability enhancers iswithin the skill of the art.

[0114] G. Cost

[0115] Lithium is the least expensive drug used in psychiatric practice.Cost savings can also occur if interchangeable drug reservoirs are usedwith a battery/current source/backing system to lower the total cost ofdaily patch replacement. Also the use of continuous as opposed to pulseddc as the iontophoretic driving force for Li⁺ delivery simplifies patchdesign and reduces cost.

[0116] 7. Mental Disorders Suitable for Treatment with Patch Technology

[0117] The typical mental disorders suitable for treatment with patchtechnology of the present invention include acute mania and bipolar(manic/depressive) disorder, as defined in Frances, A. et al. (Eds.)Diagnostic and Statistical Manual of Mental Disorders Fourth EditionAmerican Psychiatric Association 1994. Some of the significantcharacteristics of the technology of the present invention includebetter control of drug delivery and of patient compliance, featuresmaking the technology suitable for expanded use of lithium in thetreatment of disabling mood disorders and other psychiatric illnesses.

EXAMPLE 1

[0118] Sherry F. is a 42 year old female with a long history ofmanic-depressive illness. Her mood swings are extreme and when manic shebecomes paranoid, hyperactive and engages in a number of activities thatare dangerous to her, including spending sprees, speeding while drivingand sexual promiscuity. Although she responds well to treatment withlithium, she is unfortunately unable to tolerate the side effects ofeither the generic immediate release form of lithium carbonate or theslow release lithium preparations. She experiences severegastrointestinal upset, nausea and diarrhea when her lithium doseadministered orally exceeds 900 mg per day. However, she requires1500-1800 mg per day to control her symptoms. Because she is unable totolerate the doses of lithium required to maintain her symptoms, she hasbeen treated with a variety of other medications, includingcarbamazepine, a typical antipsychotics and valproic acid, all withserious drawbacks in terms of side effects. The application of thetransdermal patch of the present invention is suitable to obtainsufficient lithium plasma concentrations without the GI upset.

EXAMPLE 2

[0119] Roger S. is a 20 year old man who was institutionalized at acenter within a state hospital system for children and adults who aredevelopmentally disabled. Because of trauma associated with birth andassociated hypoxia, Roger S. suffered considerable brain damage and,although physically healthy, he suffers from an impulse control disordercharacterized by self injury and injury to others. For that reason hehas been hospitalized for the last 12 years. He is unwilling tocooperate with taking oral medications and, although lithium has beenshown to stabilize his mood and markedly reduce his outbursts, he isunwilling to cooperate with nursing staff to take it. The transdermalpatch according to the present invention applied once or twice a week issuitable for treating this patient.

EXAMPLE 3

[0120] Peggy R. is a 37 year old female with a long history ofintractable and severe depression. She has failed a treatment with avariety of standard antidepressants. Three suicide attempts are known.Lithium converts antidepressant non-responders to responders inapproximately 50% of patients who do not respond to antidepressantmonotherapy. Application of the transdermal patch of the presentinvention is suitable to maintain her current antidepressant regimen,minimize the side effects of lithium and to improve her treatmentresponse to the antidepressant.

EXAMPLE 4

[0121] Patty G. is an 11 year old girl with a two year history ofbipolar disorder in childhood. She has marked temper tantrums,irritability, violent outbursts and wild mood swings. Although she hasresponded to treatment with lithium, she is unable to comply with orallyingesting lithium tablets three times per day. Application of thetransdermal patch of the present invention is suitable for providingsubstantially constant levels of lithium with minimal side effects.

[0122] While the foregoing specification teaches the principles of thepresent invention, with examples provided for the purpose ofillustration, it will be understood that the practice of the inventionencompasses all of the usual variations, adaptations, or modifications,as come within the scope of the following claims and its equivalents.

What is claimed is:
 1. A method for administering lithium at asubstantially constant rate without causing significant pain or tissuedamage to a human patient in need thereof, which method comprises: (a)providing a source of iontophoretically deliverable lithium; and (b)iontophoretically delivering Li⁺ to said patient.
 2. The method of claim1, further comprising monitoring the blood Li⁺ concentrations andadjusting the dose rate if necessary to provide and maintain blood Li⁺concentrations of between about 0.6 and about 1.4 mEq/L.
 3. The methodof claim 1, wherein the source of iontophoretically deliverable lithiumis a dermal patch.
 4. The method of claim 3, wherein the dermal patchcomprises a current distribution member capable of delivering currentsufficient to iontophoretically deliver Li⁺ across a stratum corneum ofan epidermis of said human.
 5. The method of claim 4, wherein saidcurrent is direct current.
 6. The method of claim 5, wherein said directcurrent is pulsed direct current.
 7. The method of claim 4, wherein saidcurrent is provided at a density in the range of from about 50 to about350 μA/cm².
 8. The method of claim 7, wherein the current density isbetween about 50 and about 200 μA/cm².
 9. The method of claim 6, whereinthe pulsed direct current has a pulse frequency between about 1 andabout 10 kHz.
 10. The method of claim 9, wherein the pulse frequency isabout 4 kHz.
 11. The method of claim 9, wherein patch has an on:offratio duty cycle between about 1 and about 99%.
 12. The method of claim11, wherein the on:off ratio duty cycle is about 75%.
 13. The method ofclaim 4, wherein the current distribution member does not cause orreduces skin irritation or discoloration or both.
 14. The method ofclaim 13, wherein the current distribution member is an Ag/AgCl mesh.15. A method of treating in humans acute mania or bipolar(manic/depressive) disorder comprising the steps of (a) topicallyapplying to the skin of a patient in need of such treatment atransdermal delivery system comprising a source of lithium, and (b)delivering an effective amount of lithium ion to the patient'sbloodstream.
 16. A dermal patch for administering lithium to a humanpatient at substantially constant rate without causing significant painor tissue damage, which patch comprises: a source of lithium foriontophoretic delivery; a support for said lithium source; a currentdistribution member for delivering a pulsed direct current sufficient toiontophoretically deliver lithium across a stratum corneum layer of theepidermis of said human, said current distribution member comprising anelectrochemically active component in electrical connection with abattery, a voltage pulse generator and a precision resistor; and adetoxification or neutralization effective amount of a complexing agentselected from EDTA or EGTA or pharmaceutically acceptable salts thereof;wherein the lithium source is unbuffered; and wherein the patch issubstantially free of any skin permeability enhancers.
 17. A method oftreating acute mania or bipolar (manic/depressive) disorder withlithium, by providing and maintaining blood Li⁺ concentrations ofbetween about 0.6 and about 1.4 mEq/L in humans in need thereof, whichmethod comprises the steps of (a) providing a dermal patch foradministering lithium to a patient at substantially constant rate; (b)attaching the patch to the patient's skin; (c) iontophoreticallydelivering Li⁺ from said patch to the patient.
 18. The method of claim17, further comprising monitoring the blood Li⁺ concentrations andadjusting the dose rate if necessary to provide and maintain blood Li⁺concentrations of between about 0.6 and about 1.4 mEq/L.
 19. The methodof claim 17, wherein the dermal patch comprises: a source of lithium foriontophoretic delivery; a support for said lithium source; a currentdistribution member for delivering a pulsed direct current sufficient toiontophoretically deliver lithium across a stratum corneum layer of theepidermis of said human, said current distribution member comprising anelectrochemically active component in electrical connection with abattery, a voltage pulse generator and a precision resistor.
 20. Themethod of claim 19, wherein the electrochemically active component ofthe patch comprises an Ag/AgCl mesh.
 21. The method of claim 19, whereinthe source of lithium is LiCl, lithium carbonate, or lithium nitrate, orcombination thereof.
 22. The method of claim 19, wherein the support forlithium in the patch comprises a drug reservoir, a tamper-proofocclusive backing, a conductive gel, and a membrane permeable to Li⁺suitable for contact with the epidermal layer of the skin.
 23. Themethod of claim 22, wherein the support further comprises an adhesive.24. The method of claim 17, wherein the lithium source is unbuffered.25. The method of claim 17 further comprising detoxification orneutralization effective amount of a complexing agent selected from thegroup consisting of EDTA, EGTA, and pharmaceutically acceptable saltsthereof.
 26. The method of claim 17, wherein the patch is substantiallyfree of skin permeability enhancers.
 27. A method of treating acutemania or bipolar (manic/depressive) disorder with lithium, by providingand maintaining blood Li⁺ concentrations of between about 0.6 and about1.4 mEq/L in humans in need thereof, which method comprises the stepsof: (a) providing a dermal patch for administering lithium to a patientat substantially constant rate without causing significant pain ortissue damage; (b) attaching the patch to the patient's skin; (c)iontophoretically delivering Li⁺ from said patch to the patient; whereinthe dermal patch for administering lithium to a patient at substantiallyconstant rate comprises: a source of lithium for iontophoretic delivery;a support for said lithium source; a current distribution member fordelivering a pulsed direct current sufficient to iontophoreticallydeliver lithium across a stratum corneum layer of the epidermis of saidhuman, said current distribution member comprising an electrochemicallyactive component in electrical connection with a battery, a voltagepulse generator and a precision resistor; and a detoxification orneutralization effective amount of a complexing agent selected from thegroup consisting of EDTA, EOTA, and pharmaceutically acceptable saltsthereof; wherein the patch lithium source is unbuffered, and wherein thepatch is substantially free of skin permeability enhancers.
 28. A dermalpatch for administering lithium to a human patient at substantiallyconstant rate without causing significant pain or tissue damage, whichpatch comprises: a source of lithium for iontophoretic delivery; asupport for said lithium source; a current distribution member fordelivering a pulsed direct current sufficient to iontophoreticallydeliver lithium across a stratum corneum layer of the epidermis of saidhuman, said current distribution member comprising an electrochemicallyactive component in electrical connection with a battery, a voltagepulse generator and a precision resistor.
 29. The dermal patch of claim28, wherein the electrochemically active component comprises an Ag/AgClmesh.
 30. The dermal patch of claim 28, wherein the source of lithium isLiCl, lithium carbonate, or lithium nitrate, or combination thereof. 31.The dermal patch of claim 28, wherein the support for said lithiumsource comprises a drug reservoir, a tamper-proof occlusive backing, aconductive gel, and a membrane permeable to Li⁺ suitable for contactwith the epidermal layer of the skin.
 32. The dermal patch of claim 31,further comprising an adhesive.
 33. The dermal patch of claim 28,wherein the lithium source is unbuffered.
 34. The dermal patch of claim31, further comprising a detoxification or neutralization effectiveamount of a complexing agent selected from the group consisting of EDTAor EGTA or pharmaceutically acceptable salts thereof.
 35. The dermalpatch of claim 28, wherein the patch is substantially free of skinpermeability enhancers.
 36. The dermal patch of claim 28, wherein thepatch is substantially free of ethylene glycol.